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J Med Chem. 2010 Jan 14;53(1):402-18. doi: 10.1021/jm9013482.

Synthesis and opioid receptor binding affinities of 2-substituted and 3-aminomorphinans: ligands for mu, kappa, and delta opioid receptors.

Author information

1
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.

Abstract

The phenolic group of the potent mu and kappa opioid morphinan agonist/antagonists cyclorphan and butorphan was replaced by phenylamino and benzylamino groups including compounds with para-substituents in the benzene ring. These compounds are highly potent mu and kappa ligands, e.g., p-methoxyphenylaminocyclorphan showing a K(i) of 0.026 nM at the mu receptor and a K(i) of 0.03 nM at the kappa receptor. Phenyl carbamates and phenylureas were synthesized and investigated. Selective o-formylation of butorphan and levorphanol was achieved. This reaction opened the way to a large set of 2-substituted 3-hydroxymorphinans, including 2-hydroxymethyl-, 2-aminomethyl-, and N-substituted 2-aminomethyl-3-hydroxymorphinans. Bivalent ligands bridged in the 2-position were also synthesized and connected with secondary and tertiary aminomethyl groups, amide bonds, and hydroxymethylene groups, respectively. Although most of the 2-substituted morphinans showed considerably lower affinities compared to their parent compounds, the bivalent ligand approach led to significantly higher affinities compared to the univalent 2-substituted morphinans.

PMID:
19928862
PMCID:
PMC2814335
DOI:
10.1021/jm9013482
[Indexed for MEDLINE]
Free PMC Article

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